tbuckley/cabot-search huggingface dataset:
Survival outcomes following colorectal cancer surgery in low- and middle-income countries: A systematic review.
Authors: Tom M. Diehl, Adel H. Khan, Nabiha Akhlaq Mughal, Daniel T. Schroeder, Sheida Pourdashti, Leslie Christensen, Sadaf Khan, Syed Nabeel Zafar
Journal: Journal of Clinical Oncology (2022)

3544 Background: Colorectal cancer (CRC) is a surgical disease that ranks among leading causes of global deaths, but little is known about survival outcomes following CRC surgery in low- and middle-income countries (LMICs). In this study, we sought to review all published literature on long-term outcomes following CRC resections in LMICs. Methods: We completed a systematic review of original research articles presenting survival outcomes after CRC resection with curative intent in LMICs. Databases searched included PubMed, Web of Science, Embase, and Global Index Medicus. Country income groupings were determined by 2020 World Bank data. We excluded articles involving pediatric populations (&lt;18 years), non-primary colorectal cancers, benign disease, and endoscopic/transanal resection only. Articles published before 2005 or without English full text were also excluded. Abstracts and full texts were assessed for eligibility by two independent reviewers; conflicts were resolved by a third reviewer. Data from China dominated the published literature and were excluded from final analysis. Survival data were extracted for 5-year disease free survival (DFS) and overall survival (OS). Results: Our search returned 29,134 articles. After automated and manual deduplication, 18,849 abstracts were assessed for eligibility. Following abstract and full-text review, 583 articles met the inclusion criteria for the study. Table 1 shows the most-represented countries and their associated income levels. In total, 1/27 low-income countries, 11/55 lower-middle income countries, and 16/55 upper-middle income countries were represented, which accounted for 0.3%, 12.9% and 86.8% of all included articles, respectively. The majority of articles were from China (379/583; 65%). Excluding data from China, 5-year disease DFS and OS varied significantly across included studies: Stage I = 64-100% DFS and 70-100% OS; Stage II = 75-94% DFS and 50-94% OS; Stage III = 34-87% DFS and 20-93% OS; Stages I-III combined = 53-86% DFS and 29-97% OS. Conclusions: There is a dearth of data on long-term outcomes following CRC operations in LMICs, especially among low-income countries. OS ranges markedly by country income group highlighting global disparities in cancer care. Our review emphasizes a dire need for cancer research capacity building in LMICs. [Table: see text]
LB101, a conditionally tetravalent PD-L1xCD47 bispecific monoclonal antibody (mAb), combines tumor microenvironment (TME) targeted delivery (PD-L1) and a single biological high potency effector (CD47).
Authors: Jonny Finlay, Antoine Yver, Simon Chivers, David Grainger
Journal: Journal of Clinical Oncology (2022)

2562 Background: Anti-PD-L1 antibodies are well-established as potent immune effectors in solid tumors expressing PD-L1 and demonstrate binding to these tumor cells within the TME. By contrast, due to the ubiquitous expression of CD47 on normal cells and tissues, anti-CD47 therapeutic agents with an active antibody Fc can lead to serious dose-limiting toxicities and profound biodistribution problems. To overcome these issues, we have generated LB101, a next-generation conditionally activated PD-L1xCD47 bispecific mAb with two anti-CD47 domains blocked by two further anti-PD-L1 domains, linked by two proprietary IgG-derived hinges, which inhibit CD47 interactions in the periphery, but are degraded in the PD-L1+ TME, thereby activating CD47 blockade to induce antibody-dependent cellular phagocytosis (ADCP). Methods: An IgG1-based, conditionally activated bispecific molecule was examined in binding, phagocytosis, PD-L1 blocking and flow cytometry assays. Efficacy analyses were performed in an hPD-L1+ syngeneic model in hPD-L1+/hPD1+ C57BL/6 mice, and preliminary safety and exposure analyses were completed in monkey. Results: In its intact locked form, LB101 exhibited anti-PD-L1 assay potency similar to atezolizumab. CD47 binding was only observed for LB101 after unlocking by hinge linker cleavage, leading to strongly enhanced ADCP by human CD14+ cells. In monkey, plasma stability of the locked construct was established with a PK profile mimicking that of a typical PD-L1 mAb. In the MC38 mouse model, systemically administered LB101 monotherapy delivered at equimolar dose to atezolizumab, led to no anemia, weight-loss, or overt toxicity. Monotherapy LB101 exhibited greatly improved efficacy and durability of response (14/16 tumors eradicated) over isotype control IgG (0/16) and atezolizumab (1/16). The CD47 naked parent IgG1 mAb was not tolerated in mouse, with 100% lethality above 2mg/kg. In rechallenge experiments, all naïve mice established tumors rapidly while none of the mice from groups with prior LB101-induced regressions exhibited tumor growth. Conclusions: Single agent LB101 immunotherapy delivered systemically in a difficult to treat syngeneic mouse model resulted in PD-L1 directed, local tumor-specific CD47 effector engagement leading to significant tumor regressions as compared to atezolizumab without overt toxicity. Future developments will focus on developing LB101 as a single agent therapeutic and exploring the potential of LockBody technology in improving the therapeutic index of other anti-cancer biological effectors through conditional activation within the TME.
Four-year follow-up from a phase 2 study of obinutuzumab, ibrutinib, and venetoclax in CLL.
Authors: Kerry Anne Rogers, Ying Huang, Lynne Abruzzo, Seema Ali Bhat, Tzyy-Jye Doong, Adam Kittai, Arletta Lozanski, Gerard Lozanski, Margaret Lucas, Kami J. Maddocks, Charelen Mao, Megan Nussbaum, Ellen J Sass, Swetha Suresh, John C. Byrd, Jennifer Ann Woyach
Journal: Journal of Clinical Oncology (2022)

7540 Background: Targeted agent combinations for chronic lymphocytic leukemia (CLL) have resulted in safe regimens with improved progression-free survival (PFS) compared to chemoimmunotherapy. The optimal regimen and long-term outcomes remain unknown. We conducted a phase 2 study of obinutuzumab (OBIN), ibrutinib (IBR), and venetoclax (VEN) in relapsed/refractory (RR) and treatment-naïve (TN) CLL patients (pts) and report extended follow up on two previously reported cohorts (RR, TN 1) and a new cohort of identically treated TN pts (TN 2). Methods: Pts with TN or RR (≥1 prior treatment) CLL requiring treatment were eligible. Treatment was given for 14 28-day cycles (C). OBIN was started C1, IBR C2, and VEN C3 with standard dose escalation. Response was assessed 2 months (mos) after C14 (EOT) by iwCLL 2008 criteria. Minimal residual disease (MRD) was measured by 10-color flow cytometry with a cutoff of &lt; 1x10 -4 . The primary endpoint was complete remission (CR) with undetectable MRD (uMRD) in blood and bone marrow at EOT. A sample size of 25 pts per cohort achieves 90% power to test the null hypothesis of 10% against 30% with 1-sided α of 10%. The Kaplan-Meier method was used to estimate PFS and overall survival (OS). Results: 75 pts were treated in 3 cohorts (Table). Data are as of 1/3/2022. In the TN 2 cohort, the overall response rate (ORR) at EOT was 96% (95% CI: 80-100) and CR with uMRD was 20% (95% CI: 7-41). The ORR for TN 1 and TN 2 combined was 90% (95% CI: 78-97) and CR with uMRD was 24% (95% CI: 13-38). Median follow up was 56 (0-65), 57 (7-63), and 30 (24-35) mos, respectively, for RR, TN 1, and TN 2. There were 3 deaths (RR = 1, TN 1 = 1, TN 2 = 1) and 6 disease progressions (RR = 4, TN 1 = 2, TN 2 = 0). Estimated 48-month PFS for TN 1 and RR cohorts were both 96% (95% CI: 72-99) and OS was 85% (95% CI: 60-95) and 100%, respectively. The estimated 24-month PFS and OS for TN 2 were both 96% (95% CI: 75-99). The most frequent adverse events were neutropenia (95%, 73% grade ≥3), leukopenia (95%, 45% grade ≥3), lymphopenia (93%, 40% grade ≥3), and thrombocytopenia (91%, 28% grade ≥3). The only grade ≥3 non-hematologic toxicity occurring at ≥20% was hypertension (85%, 39% grade ≥3). Atrial fibrillation occurred in 11% of pts. Conclusions: At extended follow-up, remissions remain durable after fixed duration OBIN, IBR, and VEN. The efficacy and acceptable safety justify further study and are being compared to IBR and OBIN in 2 phase 3 US cooperative group trials. Clinical trial information: NCT02427451. [Table: see text]
HER2 in uterine carcinosarcoma: Testing platforms and implications for targeted therapy.
Authors: Navin Maredia, Sharon Wu, Alex Farrell, Matthew James Oberley, Lauren Thomaier, Nathaniel L. Jones, Thomas J. Herzog, Premal H. Thaker, Matthew A. Powell, Tenley Klc, Britt Kristina Erickson
Journal: Journal of Clinical Oncology (2022)

5590 Background: Uterine carcinosarcomas (UCS) are rare, aggressive tumors accounting for 5% of all uterine cancers. Recurrence rates are high and 5-year survival is only 18-39%. HER2 is an emerging prognostic and therapeutic target in uterine cancer including UCS. Testing algorithms and platforms in breast and gastric cancers are well studied and validated, but optimal HER2 testing in uterine cancer is not yet established. We aimed to determine HER2 prevalence in UCS and the concordance of chromogenic in situ hybridization (CISH), immunohistochemistry (IHC), and next generation sequencing (NGS) platforms to aid in the development of UCS specific testing guidelines. We also evaluated the rate of downstream mutations and immune biomarkers that may affect response to HER2 directed therapy. Methods: Eight hundred and seventy-five UCS tumor samples (primary 81.4%; metastatic 17.1%; unknown 1.5%) were analyzed using NGS (592, NextSeq; WES, NovaSeq, Caris Life Sciences, Phoenix, AZ). A subset of tumors with HER2 positivity were tested with IHC (4B5, Ventana) and/or CISH (INFORM DUAL HER2 ISH Assay, Ventana) based on 2018 ASCO/CAP HER2 Breast Cancer guidelines. Amplification of ERBB2/HER2 by NGS used a copy number cut-off &gt;6. PD-L1 expression was analyzed by IHC (SP142, positive cut-off ≥1%, Ventana). Tumor mutational burden (TMB) was measured by counting all somatic mutations found per tumor (TMB high cut-off &gt; 10 mutations per Mb). Microsatellite instability (MSI) was tested by fragment analysis (FA), IHC and NGS. Results: Rates of HER2 positivity were 3.4% (28/820) by NGS. Among the IHC/CISH-tested cohort, 7.2% was positive (10/139) by IHC, and 19.5% (27/133) by CISH. In the 105 samples tested with both IHC and CISH, the concordance was 100%. Specifically, 9/105 patients (8.6%) were IHC+/CISH+ and 96 patients (91.4%) were IHC-/CISH-. The concordance between CISH and NGS (N = 127) was 90.6% (sensitivity 100% and specificity 89.3%). Common gene alterations in CISH HER2+ UCS tumors that may implicate resistance to HER2 targeted therapy included mutations in TP53 (100%), FBXW7 (22.2%), PIK3CA (33.3%), PIK3R1 (18.5%), PTEN (3.7%) and KRAS (3.7%) and gene amplification of KRAS (11.1%). CISH+ HER2+ UCS tumors had low immunotherapy biomarker prevalence (0% MSI-H, 0% TMB high, 7.7% PD-L1+). Conclusions: Increased HER2 positivity was detected via CISH testing compared to IHC and NGS, which may reflect the heterogeneity of HER2 amplification due to mixed histology between the sarcoma and carcinoma portion of the tumor. High concordance rates were observed between CISH and IHC. These testing platforms need to be validated by response to HER2 targeted therapies in order to develop UCS specific testing guidelines.
Maturation of overall survival (OS) in TIVO-3 with long-term follow-up.
Authors: Brian I. Rini, Sumanta K. Pal, Bernard Escudier, Michael B. Atkins, David F. McDermott, Elena Verzoni, Camillo Porta, Vijay Kasturi, Thomas E. Hutson
Journal: Journal of Clinical Oncology (2022)

4557 Background: Maturity of survival data is a consideration in the value assessment and confident clinical application of oncology drugs based on trial evidence. TIVO-3 supported FDA-approval of tivozanib (TIVO) in relapsed/refractory (R/R) advanced RCC, meeting the primary endpoint of significantly improved PFS over sorafenib (SOR) (HR: 0.73, 95% CI, 0.56-0.95). Long-term follow-up analyses demonstrate that the PFS rate at 3-years with TIVO is &gt;5x higher than with SOR (12% vs 2%, respectively), yet a significant OS benefit for TIVO has not been observed to date. Here we report the contribution of event accumulation and data maturation on the stability of KM survival estimates. Methods: Intent-to-treat analyses of Cox proportional hazards and log-rank statistics were used to estimate the HR and 95% CI for OS in the TIVO-3 trial at prespecified (2-years after last-patient-in [LPI]; ≥251 events) and exploratory extended follow-up timepoints (≥270 events; database closure). Patients were followed for survival until death, consent withdrawal, or loss to follow-up. Results: 350 patients were randomized 1:1 to TIVO (n=175) or SOR (n=175). 2-years post LPI and a mean follow-up of 17.9 months (data cut-off August 2019), 65% of patients experienced an event (HR: 0.99, 95% CI, 0.76-1.29). Subsequent analyses are reported at 20.3 (May 2020), 21.9 (January 2021), and 22.8 (May 2021) months follow-up. Accumulation of events and HR over time is shown in the Table. After almost 23 months of follow-up and realization of 80% of events, OS HR has decreased to below 0.90, in favor of TIVO. Conclusions: Serial OS analyses using KM estimates are subject to increased curve reliability with decreased censoring and limited residual patients at risk for death. Long-term follow-up of TIVO-3 suggests early and consistent PFS benefit with TIVO over SOR is associated with an OS HR decline over-time with more events. Clinical trial information: NCT02627963. [Table: see text]
Precision medicine: Novel PI3K inhibitor as cancer treatment.
Authors: Kasen Reed Hutchings, Patrick Beck, Rebecca Qiu, Vincent Bui, Zhi Sheng
Journal: Journal of Clinical Oncology (2022)

e15093 Background: Phosphoinositide 3-kinase (PI3K) is an attractive anti-cancer drug target due to its promotion of cell growth and proliferation; however, available pan-PI3K inhibitors currently lack specificity, leading to excessive drug toxicity and adverse effects. Selectide-18 is a novel PI3K inhibitor that targets PI3K’s catalytic subunit p110β, resulting in reduced viability of cancer cells. The p110β subunit is the most prominent PI3K subunit in many chemoresistant tumors. Previous research has revealed a unique 18-residue long motif within the C2 domain of p110β. This motif is not found in other catalytic subunits (p110α, p110δ, or p110γ), making it a promising drug target. Selectide-18 is a memetic peptide drug modeled after this motif and has been shown to effectively inhibit p110β binding without affecting other isoforms, separating it from currently available pan-PI3K inhibitors. While Selectide-18 has been successful in inhibiting PI3K in previous studies, it has poor cell permeability due to its large size. Previous findings have revealed functional redundancies among Selectide-18’s residues. This study aims to remove these redundancies and determine the optimal formulation of Selectide-18 through in silico analysis. Methods: An in silico protocol was developed to determine the optimal formulation of Selectide-18. By utilizing the PEP-FOLD server, 455 peptide models were created using 91 unique fragments of the Selectide-18 amino acid sequence ranging in size from 6 to 17 residues. Physical conformation of each model was compared to wild-type Selectide-18 using root-mean-square deviation data collected using PyMOL and UCSF Chimera software. Computational docking through AutoDock Vina was performed to test the binding affinity of each model to the active site of regulatory subunit p85α. The distance between each drug and the active site was measured with UCSF Chimera’s distance function. Finally, ClusPro docking of drug-bound p85α/p110β was compared to wild-type p85α/p110β, as well as non-truncated Selectide-18-bound p85α/p110β. Statistical significance was determined using a Student's t-test. Results: Select truncated models demonstrated physical confirmation (RMSD = 0.024), binding affinity (-8.74 kcal/mol), and simulated inhibitory capabilities comparable to Selectide-18. A specific group of variants comprised of 9 amino acids (9 residue_6K-14Q) had the shortest formulation without significant declines in binding affinity. Conclusions: Selectide-18 is a selective PI3K inhibitor that can be optimized by removing functionally redundant amino acids. A 9-residue variant ranging from amino acids 6 Lys to 14 Gln showed the most promise and will be used in future studies to reformulate Selectide-18. Being half the size of Selectide-18, this optimized drug is anticipated to have improved cell permeability without sacrificing inhibitory function.
Safety and efficacy of glasdegib in combination with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma: Phase Ib/II GEINO 1602 trial.
Authors: María Ángeles Vaz, Regina Gironés, Sonia Del Barco, Juan Manuel Sepulveda Sanchez, Miriam Alonso, Estela Pineda, Carmen Balana, María Martínez-García
Journal: Journal of Clinical Oncology (2022)

2060 Background: Hedgehog signaling through Smoothened (SMO) protein in gliomas promotes cell cycle progression and leads to glioma stem cells (GSCs) maintenance, which constitutes one of the key hallmarks for glioblastoma (GB) resistance against anticancer therapies. Glasdegib, a SMO inhibitor, may disrupt GSCs and lead to enhanced efficacy of the Stupp scheme. Methods: Newly diagnosed GB pts received glasdegib with standard radiotherapy (RT)/ temozolomide (TMZ) followed by maintenance with glasdegib monotherapy. The primary objective was to determine the recommended phase 2 dose (RP2D) in a 3+3 dose escalation (DE) strategy in phase Ib and overall survival (OS) in phase II. Secondary objectives included progression-free (PFS) according to RANO criteria, safety, changes in performance status, and exploratory biomarker analysis. Results: Between 2018 and 2020, 79 GB pts were enrolled and 78 received at least one dose of glasdegib. In DE, 4 pts received Glasdegib at 100 mg/QD and 6 pts received 75 mg/QD. DLTs were reported in 3/4 pts in 100 mg dose level, and 1/6 pts in 75 mg dose level, declaring 75 mg/QD of glasdegib as RP2D. For phase II, 68 additional pts were treated at 75 mg/QD dose. The median age was 55 years (range: 28-78), 54% were male, 45% were MGMT unmethylated, and 1 pts had an IDH1/2 mutation. Glasdegib treatment lasted a median of 6 m (range: 0.5-21.9). Overall, 72 (97.3%) pts completed concomitant therapy, 65 (87.8%) started adjuvant therapy, 28 (37.8%) completed adjuvant therapy, and 23 (31.1%) continued glasdegib monotherapy. Treatment combination was discontinued due to treatment-related adverse events (TRAEs) in 9 (12.2%) pts. For those pts that received RT/TMZ combined with glasdegib at 75 mg/QD dose, 7 (9.5%) presented grade (G) ≥3 hematological TRAEs during concomitant treatment and 2 (3.1%) during the adjuvant treatment. There were no G≥3 TRAEs of any type during the maintenance phase. Neutrophil count decrease G≥3 was reported in 6 (8.1%) pts and platelet count decrease G≥3 in 7 (9.5%) pts. Cutaneous events G≥3 were reported in 3 (4.1%) pts. ECOG, Minimental and Barthel indexes, were maintained when comparing baseline with end of treatment (p = 0.181, 0.25 and 0.346 respectively). Stabilization was the most common response, reported in 60 (81.1%) pts. After a median follow up of 7.8 m (range 0.7-25.9), median PFS was 6.9 m (95% CI: 6.1-8.5). The 6-m PFS rate was 62.1% (95% CI: 50.9-75.8) and the 18 m OS rate was 63.3% (95% CI: 47.5-84.4). Conclusions: The addition of glasdegib to standard RT and TMZ was safe. Glasdegib monotherapy showed no G ≥3 TRAEs. Most patients had disease stabilization, with a promising preliminary PFS and OS for newly diagnosed GBM. Final survival results are awaited. Clinical trial information: NCT03466450.
Prognostic value of beta 2-microglobulinin (β2MG) in cerebrospinal fluid (CSF) in primary central nervous system lymphoma (PCNSL).
Authors: Alexandre Bertucci, Celine Boucard, Vincent Harlay, Olivier L. Chinot, Emeline Tabouret
Journal: Journal of Clinical Oncology (2022)

e14047 Background: Prognosis and response assessment are crucial to guide PCNSL patient therapeutic management. β2MG is a well-known prognostic factor of systemic lymphoma but its prognostic value in PCNSL remains uncertain. Objective is to evaluate the prognostic value of β2MG in CSF in PCNSL patients. Methods: We prospectively analyzed the CSF β2MG concentration in all newly PCNSL patients referred to our institution between March 2014 and November 2021 for whom lumbar punction was allowed. β2MG analysis was performed at diagnosis before the first treatment administration, after 2 and 4 treatment cycles. The clinical, radiological, histological, biological and treatment data were retrospectively collected. Results: Thirty-six patients were included with a median age of 71.8 (range 42.5 – 85.3). All patients presented with DLBCL CD20+ lymphoma. Median KPS was 70 (range, 30 – 100). Median dose of prednisone at diagnosis was 60 mg (range, 0 – 1000). Thirty-two patients (88.9%) received polychemotherapy with high-dose methotrexate as first line treatment. In CSF, median β2MG was 3.55 mg/L (range, 0.88 – 19.24), median IL10 was 35.0 pg/mL (range, 3.0 – 2843) and median IL6 was 22.1 pg/mL (range, 2.0 – 120). Only 14% and 16% of patients presented with normal CSF and blood β2MG rate at diagnosis, respectively. Five patients presented with meningitis involvement. CSF β2MG was independent from blood β2MG (p = 0.861), from CSF IL10 (p = 0.379), from CSF IL6 (p = 0.479) and from blood LDH (p = 0.685). Complete, partial responses or progressive disease were observed in 18 (54.5%), 10 (30.3%) and 5 (15.2%) patients respectively. CSF β2MG concentration tended to be correlated to patient response (p = 0.129). The rates of complete response were 65% and 44% for low (&lt; median) and high (&gt; median) CSF β2MG rates, respectively. At last follow-up, 17 patients (47%) had relapsed, and 11 patients (31%) died. Median progression-free survival (PFS) and overall survival (OS) were 21.2 months (95%CI: 5.9 – 36.4) and 47.6 months (95%CI not estimable due to the low number of events), respectively. In univariate analysis, low KPS and high CSF β2MG were associated with poor PFS (p = 0.002 and p = 0.008, respectively) with no detectable impact of blood β2MG. CSF IL10 and IL6 were not associated with patient outcome. In multivariate analysis high CSF β2MG tended to remain associated with worse PFS (p = 0.087, HR: 2.784, 95%CI: 0.862 – 8.987). In responder patients, CSF β2MG was significantly decreased at 4 months after first line treatment initiation (p = 0.005). Conclusions: CSF β2MG may exhibit a prognostic value in PCNSL patients. These results need to be validated in a larger prospective study.